Assessing CpG island methylator phenotype, 1p/19q codeletion, and MGMT promoter methylation from epigenome-wide data in the biomarker cohort of the NOA-04 trial

Wiestler, Benedikt; Capper, David; Hovestadt, Volker; Sill, Martin; Jones, David; Hartmann, Christian; Felsberg, Joerg; Platten, Michael; Feiden, W.; Keyvani, Kathy; Pfister, Stefan M.; Wiestler, Otmar D.; Meyermann, Richard; Reifenberger, Guido; Pietsch, Thorsten; Deimling, Andreas von; Weller, Michael; Wick, Wolfgang

doi:10.1093/neuonc/nou138

Cited by 84 publications

(67 citation statements)

References 39 publications

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“…patients demonstrated intermediate PFS and OS when compared to genomic group I or V patients. Again, this finding fits well to the recent NOA-04 data demonstrating intermediate survival for patients with gCIMP positive, 1p/19q intact and ATRX mutant/deficient anaplastic gliomas [39]. However, our intermediate survival group included not only patients with IDH1/2 mutant astrocytic or oligoastrocytic gliomas without 1p/19q codeletion, but also a small group of patients with IDH1/2 wild-type tumors, i.e.…”

Section: Discussionsupporting

confidence: 90%

“…Our findings thus suggest that the absence of histological features of glioblastoma, that is microvascular proliferation and necrosis, in IDH1/2 wild-type gliomas with glioblastoma-like genotypes is of prognostic relevance. In line, retrospective analyses of the NOA-04 cohort of anaplastic glioma patients and glioblastoma patients of the GGN similarly indicated a longer survival of patients with IDH1/2 wild-type anaplastic gliomas compared to patients with IDH1/2 wild-type glioblastomas [11,39]. However, this assumption would need confirmation in an independent larger cohort of patients who ideally should have received identical treatment.…”

Section: Discussionmentioning

confidence: 93%

“…Outcome seems to be determined more by age and molecular genetic features of the tumors than by the current treatment options of surgery, radiotherapy and alkylating agent chemotherapy. Molecular markers, in particular IDH1/2 mutation/gCIMP and 1p/19q codeletion, have been employed to define three major prognostic groups of WHO grade III gliomas [39]. The present study explored whether large-scale genomic or transcriptomic profiling improves prognostic stratification in comparison to histology and established molecular markers like IDH1/2 mutation and 1p/19q co-deletion in WHO grade II and III gliomas.…”

Section: Discussionmentioning

confidence: 99%

“…Prognostic evaluation of molecular subgrouping revealed the worst survival for patients whose tumors showed a glioblastoma-like genomic profile associated with IDH1/2 wild-type status, frequent gains on 7q and losses on 10q, often a classical glioblastoma-like expression profile, and mostly anaplastic astrocytic or oligoastrocytic histology (Fig. 4) [11,39]. However, this assumption would need confirmation in an independent larger cohort of patients who ideally should have received identical treatment.…”

Section: Discussionmentioning

confidence: 99%

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Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups

et al. 2015

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Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether largescale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome-and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (-10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/-10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups

et al. 2015

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“…For the detection of amplifications and chromosomal gains and losses, automatic scoring was verified by manual assessment of the respective loci for each individual profile [10,19]. The MGMT promoter methylation status and the presence of the glioma CpG island methylator phenotype (CIMP) were determined based on 450k array data [1,24].…”

Section: Patients and Neuroimagingmentioning

confidence: 99%

Gliomatosis cerebri: no evidence for a separate brain tumor entity

et al. 2015

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Gliomatosis cerebri (GC) is presently considered a distinct astrocytic glioma entity according to the WHO classification for CNS tumors. It is characterized by widespread, typically bilateral infiltration of the brain involving three or more lobes. Genetic studies of GC have to date been restricted to the analysis of individual glioma-associated genes, which revealed mutations in the isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 (TP53) genes in subsets of patients. Here, we report on a genome-wide analysis of DNA methylation and copy number aberrations in 25 GC patients. Results were compared with those obtained for 105 patients with various types of conventional, i.e., non-GC gliomas including diffuse astrocytic gliomas, oligodendrogliomas and glioblastomas. In addition, we assessed the prognostic role of methylation profiles and recurrent DNA copy number aberrations in GC patients. Our data reveal that the methylation profiles in 23 of the 25 GC tumors corresponded to either IDH mutant astrocytoma (n = 6), IDH mutant and 1p/19q codeleted oligodendroglioma (n = 5), or IDH wild-type glioblastoma including various molecular subgroups, i.e., H3F3A-G34 mutant (n = 1), receptor tyrosine kinase 1 (RTK1, n = 4), receptor tyrosine kinase 2 (classic) (RTK2, n = 2) or mesenchymal (n = 5) glioblastoma groups. Two tumors showed methylation profiles of normal brain tissue due to low tumor cell content. While histological grading (WHO grade IV vs. WHO grade II and III) was not prognostic, the molecular classification as classic/RTK2 or mesenchymal glioblastoma was associated with worse overall survival. Multivariate Cox regression analysis revealed MGMT promoter methylation as a positive prognostic factor. Taken together, DNA-based large-scale molecular profiling indicates that GC comprises a genetically and epigenetically heterogeneous group of diffuse gliomas that carry DNA methylation and copy number profiles closely matching the common molecularly defined glioma entities. These data support the removal of GC as a distinct glioma entity in the upcoming revision of the WHO classification. 3

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Diagnostic test accuracy and cost-effectiveness of tests for codeletion of chromosomal arms 1p and 19q in people with glioma

McAleenan

Jones

Kernohan

et al. 2022

Cochrane Database of Systematic Reviews

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Assessing CpG island methylator phenotype, 1p/19q codeletion, and MGMT promoter methylation from epigenome-wide data in the biomarker cohort of the NOA-04 trial

Abstract: G-CIMP and 1p/19q codeletion are reliably detectable by HM450 analysis and are associated with prognosis in the NOA-04 trial. For MGMT, HM450 suggests promoter methylation in the vast majority of G-CIMP tumors, which is supported by pyrosequencing.

Cited by 84 publications

References 39 publications

Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups

Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups

Gliomatosis cerebri: no evidence for a separate brain tumor entity

Diagnostic test accuracy and cost-effectiveness of tests for codeletion of chromosomal arms 1p and 19q in people with glioma

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